PROJECT SUMMARY Sjgren syndrome is a chronic autoimmune disease characterized by immune-mediated destruction of lacrimal and salivary glands leading to vision-threatening dry eye disease, profound dry mouth, and overall decreased quality of life. The immunopathogenesis of Sjgren syndrome is poorly understood, and treatments fail to halt the autoimmune destruction of the targeted glands. There is a critical need to identify mechanisms of disease initiation to overcome barriers to designing effective therapies. Disease initiation precedes clinical manifestations by years (even decades) precluding such studies in humans. Nonobese diabetic (NOD) mice develop spontaneous autoimmunity of lacrimal and salivary glands with several features resembling Sjgren syndrome in humans including the central role of T cells in mediating the autoimmune attack on these glands. We have recently discovered that lacrimal gland autoimmunity in NOD mice requires interleukin 27 (IL27) and type I interferons (IFN). These cytokines are complex with both immunostimulatory and immunomodulatory effects depending on the context. Thus, directly targeting IL27 or type I IFN may not be appropriate in the treatment of Sjgren syndrome. The long-term goal of our research is to identify new therapeutic targets for Sjgren syndrome. Our objectives in this proposal are to identify mechanisms by which IL27 and type I IFN drive lacrimal gland autoimmunity in the NOD mouse model of Sjgren syndrome. Our central hypothesis is that innate immune signals (eg, type I IFN) promote lacrimal gland antigen presenting cells to produce IL27, which drives pathogenic effector T cells to target lacrimal glands. Our specific aims to test this hypothesis are: (1) Identify the cellular targets of IL27 and downstream effects on effector T cells required for lacrimal gland autoimmunity; (2) Define the upstream triggers of IL27 including the role of type I IFN in driving male-specific lacrimal gland disease. We will use the NOD mouse-based spontaneous disease model, genetically edited NOD strains, our adoptive transfer model, bone marrow chimeras, and in vitro cultures to pursue these studies. The significant positive impact of completing these studies includes identifying mechanisms by which human disease-relevant cytokines drive T cell dysregulation in lacrimal gland autoimmunity, which will lead to novel therapies to halt the autoimmune attack. Given the roles of IL27 and type I IFN in other autoimmune diseases, these findings may lead to therapies for other autoimmune diseases as well.